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GABA Receptor Subunit Plasticity in Epilepsy

癫痫中的 GABA 受体亚基可塑性

基本信息

批准号：
7379931
负责人：
CAROLYN R HOUSER
金额：
$ 33.59万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Alterations in GABAA receptors (GABARs) are likely to play pivotal roles in temporal lobe epilepsy. It is now recognized that changes in specific GABAR subunits could alter the characteristics of inhibition in seizure-prone brain regions without necessarily producing a massive or generalized loss of inhibition. The delta subunit will be the focus of these studies because GABARs that contain this subunit appear to be uniquely plastic, play an important role in GABA-mediated tonic inhibition and may be major biological targets of neurosteroids in some brain regions such as the dentate gyrus. The broad hypothesis is that changes in delta subunit expression and localization could influence seizure susceptibility by altering tonic inhibition and responsiveness to neurosteroids. Changes will be studied in a pilocarpine-treated mouse model of recurrent seizures and following administration of a synthetic neuroactive steroid. A combination of light and electron microscopic immunohistochemical methods will be used to identify changes in expression and localization of the delta subunit and related GABAR subunits that include alpha4 and gamma2. The following questions will be addressed: 1) Does a decrease in delta subunit expression lead to alterations in the subcellular localization of other GABAR subunits such as gamma2 in a mouse model of epilepsy? 2) What are the morphological and functional characteristics of interneurons that express high levels of the delta subunit in normal and epileptic animals? 3) What GABAR subunits are localized with the delta subunit in neurons of the dentate gyrus? 4) Is delta subunit expression altered by chronic administration of the neuroactive steroid ganaxolone? In all studies, emphasis will be placed on evaluating potential differences between GABAR subunit changes in principal cells and interneurons in the hippocampal formation. The morphological findings will be related to physiological and biochemical studies of GABARs in other components of this program project. The studies could identify new types of GABAR plasticity that could contribute to seizure activity and might also suggest cell-specific targets for pharmacological treatment of epilepsy and related disorders.

描述（由申请人提供）：GABAA受体（gabar）的改变可能在颞叶癫痫中起关键作用。现在已经认识到，特定GABAR亚基的改变可以改变癫痫易发脑区的抑制特征，而不必产生大量或普遍的抑制丧失。δ亚基将是这些研究的重点，因为含有该亚基的gabar似乎具有独特的可塑性，在gaba介导的强直抑制中起重要作用，并且可能是神经类固醇在某些脑区域（如齿状回）的主要生物学靶点。广泛的假设是，delta亚基表达和定位的改变可能通过改变强直抑制和对神经类固醇的反应来影响癫痫易感性。这些变化将在匹罗卡品治疗的复发性癫痫发作小鼠模型中进行研究，并在给予合成神经活性类固醇后进行研究。结合光镜和电镜免疫组织化学方法将用于鉴定delta亚基和相关GABAR亚基（包括alpha4和gamma2）的表达和定位的变化。以下问题将被解决：1)在癫痫小鼠模型中，delta亚基表达的减少是否会导致其他GABAR亚基（如gamma2）亚细胞定位的改变？2)正常动物和癫痫动物中高水平表达δ亚基的中间神经元的形态和功能特征是什么？3)在齿状回神经元中，哪些GABAR亚基与δ亚基一起定位？4)长期服用神经活性类固醇加那洛酮会改变δ亚基表达吗？在所有的研究中，重点将放在评估海马结构中主细胞和中间神经元中GABAR亚基变化的潜在差异。形态学发现将与该项目其他组成部分的gabar的生理和生化研究相关。这些研究可以确定新的GABAR可塑性类型，可能有助于癫痫活动，也可能为癫痫和相关疾病的药物治疗提供细胞特异性靶点。